Fatal familial insomnia

Summary

Fatal familial insomnia (MONDO:0010808) is a disease with 1 cohort gene and 2 clinical trials. Top therapeutic interventions include doxycycline hydrochloride.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 14
• Phenotypes (HPO): 34
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		27	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0000726	Dementia	Very frequent (80-99%)
HP:0001336	Myoclonus	Very frequent (80-99%)
HP:0012332	Abnormal autonomic nervous system physiology	Very frequent (80-99%)
HP:0100785	Insomnia	Very frequent (80-99%)
HP:0000712	Emotional lability	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000738	Hallucinations	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001649	Tachycardia	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002071	Abnormality of extrapyramidal motor function	Frequent (30-79%)
HP:0006511	Laryngeal stridor	Frequent (30-79%)
HP:0006979	Sleep-wake cycle disturbance	Frequent (30-79%)
HP:0009926	Epiphora	Frequent (30-79%)
HP:0010535	Sleep apnea	Frequent (30-79%)
HP:0012660	Thalamic hypometabolism in FDG PET	Frequent (30-79%)
HP:0031843	Bradyphrenia	Frequent (30-79%)
HP:0033687	Short term memory impairment	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:5200044	Reduced attention regulation	Frequent (30-79%)
HP:5200360	Short rem sleep	Frequent (30-79%)
HP:0000651	Diplopia	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0002371	Loss of speech	Occasional (5-29%)
HP:0003118	Increased circulating cortisol level	Occasional (5-29%)
HP:0007256	Abnormal pyramidal sign	Occasional (5-29%)
HP:0012689	Abnormal pineal melatonin secretion	Occasional (5-29%)
HP:0010850	EEG with spike-wave complexes	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	fatal familial insomnia
Mondo ID	MONDO:0010808
MeSH	D034062
OMIM	600072
Orphanet	466
DOID	DOID:0050433
ICD-10-CM	A81.83
ICD-11	669154658
NCIT	C84711
SNOMED CT	83157008
UMLS	C0206042
MedGen	104768
GARD	0006429
MedDRA	10072077
NORD	1920
Is cancer (heuristic)	no

Also known as: familial fatal insomnia · fatal familial insomnia · FFI · Insomnia familial fatal

Data availability: 14 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › prion disease › fatal familial insomnia

Related subtypes (9): Creutzfeldt Jacob disease, kuru, scrapie, Gerstmann-Straussler-Scheinker syndrome, Huntington disease-like 1, spongiform encephalopathy with neuropsychiatric features, familial Alzheimer-like prion disease, PrP systemic amyloidosis, sporadic fatal insomnia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

14 retrieved; paginated sample, class counts are floors:

4 benign/likely benign, 3 uncertain significance, 2 conflicting classifications of pathogenicity, 2 pathogenic, 1 pathogenic/likely pathogenic/pathogenic, low penetrance, 1 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13399	NM_000311.3(PRNP):c.[385A>G;532G>A]		Pathogenic	no assertion criteria provided
13398	NM_000311.5(PRNP):c.598G>A (p.Glu200Lys)	PRNP	Pathogenic	criteria provided, multiple submitters, no conflicts
13403	NM_000311.5(PRNP):c.628G>A (p.Val210Ile)	PRNP	Pathogenic/Likely pathogenic/Pathogenic, low penetrance	criteria provided, multiple submitters, no conflicts
39359	NM_000311.5(PRNP):c.532G>A (p.Asp178Asn)	PRNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1326274	NM_000311.5(PRNP):c.635A>C (p.Gln212Pro)	PRNP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13405	NM_000311.5(PRNP):c.538G>A (p.Val180Ile)	PRNP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13406	NM_000311.5(PRNP):c.695T>G (p.Met232Arg)	PRNP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1468083	NM_000311.5(PRNP):c.498G>A (p.Met166Ile)	PRNP	Uncertain significance	criteria provided, multiple submitters, no conflicts
338656	NM_000311.5(PRNP):c.*115G>A	PRNP	Uncertain significance	criteria provided, multiple submitters, no conflicts
13397	NM_000311.5(PRNP):c.385A>G (p.Met129Val)	PRNP	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1576397	NM_000311.5(PRNP):c.636G>A (p.Gln212=)	PRNP	Likely benign	criteria provided, multiple submitters, no conflicts
338645	NM_000311.5(PRNP):c.159C>T (p.Gly53=)	PRNP	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
65494	NM_000311.3(PRNP):c.204_227del24 (p.Pro84_Gln91del)	PRNP	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
766882	NM_000311.5(PRNP):c.306G>A (p.Pro102=)	PRNP	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PRNP	Supportive	Autosomal dominant	fatal familial insomnia	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRNP	Orphanet:157941	Huntington disease-like 1
PRNP	Orphanet:280397	Familial Alzheimer-like prion disease
PRNP	Orphanet:282166	Inherited Creutzfeldt-Jakob disease
PRNP	Orphanet:356	Gerstmann-Straussler-Scheinker syndrome
PRNP	Orphanet:397606	PrP systemic amyloidosis
PRNP	Orphanet:454745	Kuru
PRNP	Orphanet:466	Fatal familial insomnia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRNP	HGNC:9449	ENSG00000171867	F7VJQ1	Alternative prion protein	gencc,clinvar

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRNP	Other/Unknown	no		Prion, Prion_copper_b_octapeptide, Prion/Doppel_prot_b-ribbon_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
CA1 field of hippocampus	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRNP	294	ubiquitous	marker	CA1 field of hippocampus, Brodmann (1909) area 23, pigmented layer of retina

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRNP	2,594

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRNP	F7VJQ1	70

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	1	475.8×	0.004	PRNP
NCAM1 interactions	1	248.3×	0.004	PRNP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of glutamate receptor signaling pathway	1	3370.4×	0.003	PRNP
negative regulation of amyloid precursor protein catabolic process	1	3370.4×	0.003	PRNP
negative regulation of dendritic spine maintenance	1	2808.7×	0.003	PRNP
regulation of calcium ion import across plasma membrane	1	2808.7×	0.003	PRNP
positive regulation of glutamate receptor signaling pathway	1	1532.0×	0.003	PRNP
dendritic spine maintenance	1	1296.3×	0.003	PRNP
negative regulation of long-term synaptic potentiation	1	1296.3×	0.003	PRNP
negative regulation of protein processing	1	1123.5×	0.003	PRNP
neuron projection maintenance	1	1123.5×	0.003	PRNP
negative regulation of interleukin-17 production	1	1053.2×	0.003	PRNP
negative regulation of activated T cell proliferation	1	1053.2×	0.003	PRNP
response to amyloid-beta	1	991.3×	0.003	PRNP
intracellular copper ion homeostasis	1	936.2×	0.003	PRNP
negative regulation of calcineurin-NFAT signaling cascade	1	936.2×	0.003	PRNP
negative regulation of amyloid-beta formation	1	887.0×	0.003	PRNP
response to cadmium ion	1	732.7×	0.003	PRNP
cellular response to copper ion	1	624.1×	0.003	PRNP
regulation of potassium ion transmembrane transport	1	624.1×	0.003	PRNP
negative regulation of interleukin-2 production	1	581.1×	0.003	PRNP
positive regulation of protein targeting to membrane	1	561.7×	0.003	PRNP
long-term memory	1	421.3×	0.004	PRNP
positive regulation of calcium-mediated signaling	1	421.3×	0.004	PRNP
cellular response to amyloid-beta	1	391.9×	0.004	PRNP
negative regulation of type II interferon production	1	383.0×	0.004	PRNP
negative regulation of T cell receptor signaling pathway	1	366.4×	0.004	PRNP
protein destabilization	1	290.6×	0.005	PRNP
positive regulation of neuron apoptotic process	1	271.8×	0.005	PRNP
positive regulation of protein localization to plasma membrane	1	271.8×	0.005	PRNP
learning or memory	1	240.7×	0.005	PRNP
cellular response to xenobiotic stimulus	1	240.7×	0.005	PRNP

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRNP	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PRNP

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PRNP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04846335	PHASE2	COMPLETED	Familiar Fatal Insomnia: Preventive Treatment With Doxycycline in Subject With Disease Risk
NCT05124392	Not specified	RECRUITING	Biomarker Profiling in Individuals at Risk for Prion Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DOXYCYCLINE HYDROCHLORIDE	3	1